Review

Polyarteritis nodosa revisited: a review of historical approaches, subphenotypes and a research agenda O. Karadag1,2, D.J. Jayne1

1Department of Medicine, University of ABSTRACT However, the majority of PAN cases Cambridge, United Kingdom; Polyarteritis nodosa (PAN) is a rare reflect a variety of phenotypes of un- 2 Hacettepe University Centre, form of primary known cause and lack a system of phe- Ankara, Turkey. with heterogeneous presentations, treat- notypic subclassification. PAN can oc- Omer Karadag, MD ments and disease course. Historical cur at any age with wide variability in David J. Jayne, MD approaches to classification and diag- organ involvement, although survival Please address correspondence to: nostic terminology are reviewed. Since and recommended treatment strategies Prof. Omer Karadag, differentiation of PAN from microscopic Hacettepe Universitesi Tip Fakultesi, broadly reflect severity. We propose that Romatoloji Bilim Dali, polyangiitis (MPA) and other ANCA vas- subphenotypes within PAN having dif- 06100 Sihhiye-Altındag, culitides by the Chapel Hill conference ferent clinical courses may be different Ankara, Turkey. statements, and with hepatitis associated diseases rather than a spectrum of the E-mail: [email protected]; PAN defined as a secondary vasculitis, same disease. There is a need to better [email protected] the phenotyping and subclassification of understand these subphenotypes to un- Received on December 27, 2017; PAN has received little attention. Mono- derpin further clinical and translational accepted on January 17, 2018. genic disorders similar to PAN have been research and improve patient outcomes. Clin Exp Rheumatol 2018; 36 (Suppl. 111): described (familial Mediterranean , This paper aims to assess the heteroge- S135-S142. adenosine deaminase-2 deficiency), and neity of the clinical spectrum of PAN © Copyright Clinical and cutaneous PAN and single organ vascu- and highlight differences between sub- Experimental 2018. litis, discussed. The overlapping pheno- phenotypes. After reviewing the his- types between PAN and other primary torical evolution of the classification of Key words: polyarteritis nodosa vasculitic syndromes and subphenotypes PAN, approaches to diagnostic termi- (PAN), vasculitis, virus within PAN are explored. This work will nology, and the similarities and differ- related PAN, familial Mediterranean underpin development of newer treat- ences of subphenotypes will be consid- fever (FMF), deficiency of adenosine ment regimens and future genetic and ered. This will form the basis for a rec- deaminase 2 (DADA2) related aetiologic studies. ommended research agenda, such as, further histopathological evaluation of Introduction specimens and autopsy materials and a The term peri/polyarteritis nodosa has genome wide association study in PAN. been used for more than 150 years as a diagnosis for patients with primary Historical background systemic vasculitis defined by the pres- Rudolf Virchow proposed that vascu- ence of a necrotising of mus- litis might occur in blood vessels and cular, ‘medium sized’ arteries with or originate in the adventitia in a treatise without . However, advances on histopathology in 1847 (3, 4). In in clinical and laboratory phenotyping 1852, Rokitansky described mesen- have led to specific syndromes, such teric aneurysms in the branch points of as (MPA) be- arteries in an autopsy case of polyarte- ing separated from an inclusive PAN ritis (5). Then Kussmaul and Maier in- categorisation. In parallel, there have troduced periarteritis to the literature been improvements in understanding of with the autopsy report from a 27-year certain causes of PAN, with hepatitis B- old tailor’s journeyman (6). related PAN defined as a ‘Vasculitis As- “A peculiar mostly nodular thickening sociated With Probable Etiology’ (1), (periarteritis nodosa) of countless ar- and the association of the monogenic teries and below the caliber of the liver disorder- Deficiency of Adenosine artery and the major branches of the Deaminase 2 (DADA2) (2) with a PAN coronary arteries of the heart, princi- Competing interests: none declared. phenotype (Fig. 1). pally in the bowel, stomach, kidneys,

Clinical and Experimental Rheumatology 2018 S-135 Definition of polyarteritis nodosa-subphenotypes / O. Karadag & D. Jayne

and biopsy of a small or medium-sized artery containing polymorphonuclear neutrophils. This study described four PAN subsets according to clinical features at presen- tation: • Positive arteriogram with abnormal AST or ALT; • Positive arteriogram, male sex; nor- mal AST and ALT; • Positive artery biopsy and neuropa- thy; negative arteriogram; • Neuropathy and weight loss >6.5 kg, negative arteriography and ar- tery biopsy. Because this classification system did not include a category for MPA, MPA cases would have been included in the PAN or hypersensitivity vasculitis cohorts.

Proposal of an international Fig. 1. Schema representing etiologic/genetic factors and subgroups of poliarteritis nodosa (PAN). consensus conference on nomenclature Less studied/related subgroups are shown in purple. of systemic vasculitides, Chapel Hill (CHCC) (13) spleen, heart and voluntary muscles, autoantibodies against extra-nuclear The name “polyarteritis nodosa- and, to a lesser extent, also in the liver, components of polymorphonuclear (PAN),” or alternatively, the name subcutaneous cell tissue, and in the granulocytes were detected in serum “classic PAN,” is restricted to disease in bronchial and phrenic arteries.” samples from patients with Wegener’s which there is arteritis in medium-sized Because inflammation was not confined granulomatosis (now granulomatosis and small arteries without involvement to the adventitia, and primary changes with polyangiitis) and called anti-neu- of smaller or microscopic vessels. were in the media, Dickson suggested trophil cytoplasm antibodies (ANCAs) The proposed distinguishing feature the name, polyarteritis nodosa (PAN) (11). The association of ANCA with a for PAN versus MPA, is the absence (7). In the 1930s, approximately 150 pauci-immune vasculitis and evidence versus the presence of vasculitis in ar- cases of PAN were reported, 20 from supporting the pathogenetic role of terioles, venules, or capillaries. By this the US and mostly from autopsies (8). ANCA led to the definition of ANCA definition, involvement of “microscop- They believed that any organ or combi- associated vasculitis as an aetiologic ic” vessels must be present in micro- nation of organs may be affected at any and phenotypically separate vasculitis scopic polyangiitis, although medium- time in the course of the disease, and subgroup. sized or small arteries can also be in- the resulting clinical manifestations volved. In contrast, PAN must have no may be bizarre in the extreme. Meetings and statements for involvement of “microscopic” vessels, As the nosology and nomenclature of classification/diagnostic criteria and including no glomerulonephritis. Ad- the systemic vasculitides became better nomenclature of vasculitides ditionally, mucocutaneous lymph node defined, PAN became less frequently The American College of syndrome was mentioned as the defin- diagnosed. Many different forms of Rheumatology (ACR) 1990 criteria ing feature that sets vasculitis were described. By the early for the classification of polyarteritis apart from PAN. 1950s, hypersensitivity vasculitis was nodosa (12) distinguished from polyarteritis nodosa According to this classification sys- The European League Against (9). Afterwards, necrotising vasculitis tem, patients with systemic vasculitis Rheumatism (EULAR)/Paediatric confined to the skin without systemic were classified as PAN if they had least Rheumatology European Society involvement – Cutaneous PAN – was three of 10 criteria: weight loss above (PReS) endorsed consensus criteria described and distinguished from PAN 4kg, , testicular pain/ for the classification of childhood in 1974. In the early 1970s, studies by tenderness, , or leg vasculitides (14) several authors suggested chronic hep- tenderness, mononeuropathy/polyneu- New updated classification scheme atitis B (HBV) infection could cause ropathy, diastolic blood pressure above split the old term PAN into classical PAN (10). 99 mmHg, elevated urea and creati- PAN, cutaneous PAN, MPA and HBV- In the 1980s immunoglobulin G (IgG) nine, HBV, arteriographic abnormality, related PAN.

S-136 Clinical and Experimental Rheumatology 2018 Definition of polyarteritis nodosa-subphenotypes / O. Karadag & D. Jayne

To classify a child as having PAN re- quired a biopsy showing a small and mid-size artery necrotising vasculitis or angiographic abnormalities (aneu- rysms or occlusions) in addition to at least two of the systemic features (skin involvement; systemic ; mononeuropathy or polyneuropathy; abnormal urine analysis and/or im- paired renal function, testicular pain or tenderness, signs or symptoms sug- gesting vasculitis of any other major organ system-gastrointestinal, cardiac, Fig. 2. MR Angiography of a patient with PAN (Courtesy of Hazirolan T, Professor in Hacettepe pulmonary, or central nervous system) University Department of Radiology, Ankara-Turkey) (CT Coronal MIP image (A), volume rendered are required. Magnetic resonance an- image (B). There is a microaneurysm at the lower parts of right kidney. And there are multiple cortical giography (MRA) was an acceptable loss areas at both kidneys. modality to assess angiographic abnor- malities firstly. Conventional angiog- litides. The percentage of committee cluding single organ vasculitis, vascu- raphy is recommended when MRA is dissatisfaction with the disease crite- litis associated with systemic disease, negative. ria or definition for PAN was 76% for and vasculitis associated with probable ACR 1990 Criteria and 59% for CHCC aetiology. Development and validation of definition. They mentioned the absence a consensus methodology for the of ANCA has diagnostic value in sus- Subgroups of PAN; subphenotypes classification of the ANCA-associated pected PAN. or distinct diseases? vasculitides and PAN for They discussed the importance of ab- Virus-associated PAN epidemiological studies (15) dominal angiography. Despite the ab- HBV, HCV, and Human immunodefi- The underlying principles of this inter- sence of evidence, the risks of formal ciency virus (HIV) have been associ- national study group (European Medi- angiography encouraged increased use ated with PAN (17-20). However, the cines Agency) were that each patient of digital subtraction angiography and prevalence of HBV-PAN has decreased should be classified into a single cat- MRA as alternatives (Fig. 2). as a result of increased HBV vaccina- egory and that there should be a mini- Due to the evidence to suggest that tion and improvements in blood bank- mum number of unclassified patients. HBV and HCV viruses induce direct ing. The coexistence of HCV and PAN- According to this algorithm a patient vessel damage via immune complex like vasculitis in medium-sized vessels with symptoms and signs characteris- formation in PAN and cryoglobuli- has been highlighted in a few reports. tics of PAN should be excluded from naemic vasculitis, they stated that the HIV-associated PAN is thought to be Wegener’s granulomatosis, Churg- names of viruses should be reflected in the most common form of HIV-associ- Strauss syndrome and MPA and have their definitions and names. ated vasculitis (20). at least one of compatible findings They subcategorised vasculitis into In the comparison of 123 HBV-associ- with histologic proof of vasculitis or primary and secondary forms. Primary ated PAN with 225 non-HBV associ- angiographic findings to diagnose as entities could move into the secondary ated PAN, the HBV-associated group PAN for epidemiological studies. The category if aetiologies were discovered. had higher disease activity, lower re- presence of histologically proven small Secondary vasculitis included vasculi- lapse risk, and had microaneurysms vessel vasculitis or glomerulonephritis tis due to infection, drugs, malignancy in mesenteric but not in renal arteries differentiates MPA from PAN. ANCA and connective tissue diseases. (18). Cutaneous manifestations seem was considered to be a feature of MPA to be more common in HCV-PAN and and not PAN. 2012 revised International CHCC predominated in older females. In HIV- Nomenclature of Vasculitides (1) associated PAN, commonly involved EULAR points to consider in the PAN was defined as ‘necrotising arteri- organs were primarily skin with pe- development of classification and tis of medium or small arteries without ripheral nerve, skeletal muscle, central diagnostic criteria in systemic glomerulonephritis or vasculitis in ar- nervous system, lung, gastrointestinal vasculitis (16) terioles, capillaries, or venules, and not tract, and kidney involvement. (20). An expert consensus group evaluated associated with ANCAs with a more There are major differences between the dissatisfaction with previous ACR clear dissociation from MPA with glo- viral-induced PAN. HBV-related PAN and CHCC criteria/definition and out- merulonephritis and ANCA positivity’. being the most severe and HIV-related lined 17 statements to consider in the This nosology also brought new en- PAN being the mildest form, relapses development of classification criteria tities for vasculitides classification are most frequent in HCV-related and and definitions in the systemic vascu- which can involve medium vessels, in- least frequent in HIV-related PAN. For

Clinical and Experimental Rheumatology 2018 S-137 Definition of polyarteritis nodosa-subphenotypes / O. Karadag & D. Jayne

HCV-related PAN, the reported dura- PAN with FMF was first noted in 1965, (1). Rheumatoid vasculitis is now rec- tion of the viral infection prior to PAN before the discovery of MEFV gene link ognised to primarily affect small to me- onset was approximately 20 years, but of FMF in 1997 (25, 26). dium-sized blood vessels, and is highly for HBV-related PAN it was usually Patients with PAN and FMF tend to heterogeneous in its clinical presenta- less than a year. HIV- and HCV-related be younger, compared to classic PAN tion (30). Cutaneous vasculitis and PAN do not bear a specific correlation patients (27). Peri-renal haematoma remain the most to viral load. is a distinctive feature in FMF-PAN common features followed by scleritis The pathological course of HBV-relat- since about 50% of patients develop and . Rheumatoid vasculitis ed PAN is thought to be a ‘type III’ re- this manifestation prior to or at diag- shares many features with PAN, albeit action where immune complexes pre- nosis. They frequently suffer from se- without the development of microa- cipitate and are trapped in vessel walls vere myalgia raising suspicion in PFM. neurysms. Histopathologic examina- causing vascular injury (21). HBs An- Survival was better in FMF-PAN than tion reveals mononuclear or neutro- tigen and anti-HBs antibody immune expected for other classic PAN. philic infiltration of the vessel walls in complexes have been demonstrated in FMF may predispose to the develop- association with features of vessel wall the vascular lesions. The presence of ment of vasculitis. Indeed, as suggest- destruction (necrosis, leukocytoclasis large masses of HbsAg immune com- ed by some authors, IgA vasculitis and and disruption of the elastic laminae). plexes in recent vascular lesions, with PAN associated with FMF may actu- Necrotising vasculitis of medium-sized lesser amounts in healing lesions and ally be features of this disease rather vessels resembling PAN can occur in their absence in healed lesion points than separate entities (24, 27). Sjögren’s syndrome, when patients towards a primary role played by the DADA2 is a recently identified auto- develop a necrotising vasculitis of me- immune complexes in the pathogenesis inflammatory diseases (28, 29). It is dium-sized arteries that resembles that of the vascular lesions. When the vi- due to autosomal recessive deleteri- found in PAN (31). rus is eliminated, this generally results ous mutations in Cat Eye Syndrome Even though, connective tissue disease in complete remission of the disease Chromosome Region 1 (CECR1) gene, related PAN is now in a different cate- without occurrence of relapses and in encoding for adenosine deaminase 2 gory of PAN following the 2012 CHCC prevention of long-term hepatic com- (ADA2). DADA2 is mainly charac- statement, there can be difficulties in plications (17). Conversely, HBV vac- terised by early-onset polyarteritis, differentiating between two primary cination might be a triggering factor for haemorrhagic and ischaemic inflammatory processes occurring in vasculitis in individuals with a genetic and hypogammaglobulinaemia (2). the same patient. Indeed, arthritis and predisposition (22). Additionally, hepatosplenomegaly, and polymyalgia can be a presenting feature In the EULAR/PReS consensus docu- mild immunodeficiencies were seen in of arteritis. Small patient numbers have ment HBV-associated PAN and non- the disease course. limited further differentiation of these hepatitis PAN are considered as two In many patients not only the clinical subgroups. Thus this concept is colored completely separate conditions (14). picture but also the histopathologic fea- as purple in the schema (Fig. 1). If clinical features, prognosis and re- tures are undistinguishable from those sponse to therapy differ, this decision of PAN. Skin biopsy has revealed a Cutaneous PAN seems logical (23). Similarly, ln the non-granulomatous, necrotising vascu- Cutaneous polyarteritis nodosa (cPAN) 2012 Chapel Hill nomenclature, HBV- litis of small and medium-sized vessels, is a variant of PAN that is limited pri- related PAN was described as a sepa- with the same histopathologic features marily to the skin (Fig. 3). It may re- rate entity ‘vasculitis associated with of PAN. These patients meet classifi- flect underlying disease, infection, or probable cause’, emphasising the role cation and diagnostic criteria for both medication use such as minocycline of infection (1). This dissociation could adult and childhood PAN. DADA2 is (32). A relationship of cPAN with in- be done also for other HCV and HIV- included in the medium-sized vessels flammatory bowel disease is also de- related PAN. However, there is no clear vasculitis, even if it can affect arteries scribed (33). answer to the question as to why only of any size. Association with DADA2 The extra-cutaneous manifestations of a small number of patients with these identifies the vasculitis as having a ge- and myalgia in infections develop PAN. netic basis, and it has been proposed CPAN occur only adjacent to the cu- to group this disease in the ‘Vasculitis taneous lesions, while they are more Monogenic diseases and monogenic with a probable cause’ according to the widespread systemic PAN (32). While diseases-related PAN CHCC (2). systemic PAN frequently is first evident Familial Mediterranean fever (FMF) is with the cutaneous findings of cPAN, the most prevalent type of periodic fever. Vasculitis associated with multi-organ involvement in systemic Among the vasculitic disorders reported systemic disease PAN is pervasive, particularly in the to be associated with FMF, IgA vasculi- Vasculitis associated with systemic dis- kidneys, heart, and liver. Progression tis, and PAN are most frequent, possibly ease generally have a prefix specifying from cPAN to systemic PAN appears followed by protracted febrile myalgia the systemic disease (e.g., rheumatoid to be rare. Only 1 of 41 patients with (PFM) (24). Actually, the association of vasculitis, lupus (SLE) vasculitis, etc.) cPAN evolved into systemic PAN dur-

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systemic vasculitis-associated neuropa- thies (SVNs). Without a specific clini- cal/laboratory marker, the condition depends on nerve biopsy for diagnosis. Biopsies showing necrotising vasculitis are about 50% sensitive, mandating re- liance on “suspicious” changes in many patients. Vasculitic lesions predominate in smaller epineurial vessels and are milder than those in SVNs. The disor- der is often accompanied by subclini- cal involvement of adjacent muscles and skin. Many nosologic, pathogenic, diagnostic, and therapeutic questions Fig. 3. Histopathology of a patient with cutaneous PAN (Courtesy of Arzu Saglam, Assoc Professor in Hacettepe University, Department of Pathology, Ankara-Turkey). remain unanswered. ANCA is positive A: Low power microscopy showing fibrinoid necrosis and perivascular inflammatory reaction. in some cases, without other organ fea- B: High power view where karyorrhexis can be discerned. tures of an ANCA associated vasculitis, suggesting that this subgroup has the ing the disease course in Mayo Clinic Vasculitis limited to the gastro-intes- same underlying cause as the ANCA cohort (34). Analogous findings have tinal tract can rarely be observed as a group. been reported by two other studies (2 form of SOV (41, 42). Histopathologic of 20 and 0 of 79 patients, respectively) and angiographic findings of necrotis- Primary angiitis of central nervous (33, 35). ing vasculitis limited to the GI system system (PACNS) To explore possible similarities and cannot be distinguished from PAN. Vasculitis of the central nervous system differences; a Japanese group com- There are scarce data regarding vas- can be regarded as a SOV-primary CNS pared skin biopsies from seven system- culitis limited to the GI tract. In one vasculitis when there are no features of ic PAN patients with three cPAN pa- report, 6 of 23 patients with isolated a systemic vasculitis (1). A number of tients and three with superficial venous vasculitis of GI tract progressed to sys- phenotypes have been described affect- thrombosis (36). They showed elevated temic PAN during follow-up (43). In ing different structures and vessel sizes moesin mRNA levels in the skin of pa- another, there was no progression to within the brain, some with granuloma- tients with systemic PAN, based on PAN among the patients with GI vas- tous and some with non-granulomatous real time RT-PCR compared to control culitis (34). PAN localised to the calf pathology. As with other SOV, a di- groups. Moesin is an intracellular pro- muscles with no other signs or symp- agnosis of primary CNS vasculitis re- tein that links the cell membrane and toms of more widespread involvement quires determining that CNS vasculitis cytoskeleton. Furthermore, the moesin is very rare but there are few case re- is not a component of a systemic vas- mRNA copy numbers were correlated ports published (44). culitis (e.g., GCA, MPA, GPA, EGPA), with disease activity measured by the A major dilemma is whether single or- caused by infection (e.g., syphilis), or Birmingham Vasculitis Activity Score gan PAN is really an isolated form of associated with a systemic disease (e.g., (BVAS). the disease or just the presenting symp- lupus, sarcoidosis) or part of a malig- tom of a multisystem vasculitis, for nant process, such as angiocentric lym- Single-organ vasculitis (SOV) which aggressive immunosuppressive phoma. and medium vessel involvement treatment is indicated. There are numerous reports of isolated Drug-induced PAN PAN affecting a single organ such as Organ specific (primary CNS, nerves) Clear evidence for an association with the testis, appendix, and gall bladder Vasculitis restricted to the peripheral the development of drug-induced vas- with no systemic involvement (37- nervous system (PNS), referred to as culitis has been shown for hydralazine, 39). Most cases were discovered inci- non-systemic vasculitic neuropathy anti-tumour necrosis factor-α (TNF-α) dentally when an organ was surgically (NSVN), has been described in many agents, sulfasalazine, D-penicillamine removed for unexplained symptoms or reports since 1985. Classification is and minocycline; with most evidence by misdiagnosis. complicated by the occurrence of vas- limited to case reports (46). The larg- The natural history of isolated arteritis culitic neuropathies in many systemic est series for medium vessel vasculitis of a single organ is not known (39). Al- vasculitides affecting small-to-medi- is with minocycline (47). Minocycline though histology of testicular PAN is um-sized vessels and such clinical vari- use was defined as medication use similar in isolated and systemic forms, ants as non-systemic skin/nerve vascu- at the time of onset of first symptom. the existence of infarcts in the affected litis and diabetic/non-diabetic lumbosa- Nine patients were reported; four had testis correlates more with systemic cral radiculoplexus neuropathy (45). isolated cutaneous disease, while five PAN (40). NSVN is identical to but less severe than had systemic involvement including

Clinical and Experimental Rheumatology 2018 S-139 Definition of polyarteritis nodosa-subphenotypes / O. Karadag & D. Jayne renal artery microaneurysms, cholecys- the undifferentiated/overlapped MPA/ other hand, since cPAN and macular titis, mononeuritis multiplex, and mes- EGPA/MPA group. lymphocytic arteritis share some clini- enteric vasculitis. The median duration Histopathologically, PAN, MPA and co-pathologic features, the question is of minocycline use was two years. EGPA manifest necrotising vasculitis raised whether they are not two differ- Cutaneous, as well as systemic, PAN- with fibrinoid degeneration accompa- ent entities (55). like vasculitis may occur in association nied by infiltration of inflammatory Targeted biologic therapy with B cell with minocycline use. However, these cells through all layers of artery. In ad- depletion in ANCA vasculitis (56), IL6r patients had atypical ANCA serologies dition, smaller arteries less than 500mi- blockade in (57) and and negative hepatitis B testing (47). crom in diameter are involved in EGPA IL5 blockade in EGPA (58) has shown and MPA. In clinical practice, some- proven value in clinical trials and is be- Overlapping presentations with ANCA times accessing appropriate histologic ing translated to the clinic with direct vasculitis: EGPA-PAN and MPA-PAN specimens for diagnosis is difficult. benefit for patients. Although there Currently, ANCA testing for Proteinase The overlapping features of EGPA and have been anecdotal reports of success 3-ANCA and Myeloperoxidase-ANCA PAN were proposed as a new syndrome with biologics in PAN, there have been is a key step in the differential diagno- in 1986 (51). So a phenotypic overlap no randomised controlled trials, and sis of patients with suspected vasculitis between PAN and MPA and between patients are missing out on an oppor- (48). However, patients with ANCA- PAN and EGPA should be kept in mind. tunity for improved disease control and negative AAV may have ANCA that outcomes. Combining such studies with cannot be detected with current meth- What to do next in PAN? deep phenotyping could both define pa- ods or may have ANCA of as-yet-un- There are still many unanswered ques- tient subsets by their clinical response discovered specificity, or pathogenic tions. Is there any impact of ethnicity and give insights into pathogenesis. mechanisms that do not involve ANCA and geographic area on PAN? Are there The genetic risk factors in the develop- at all may be occurring. Some patients clusters of PAN defined by genetic or ment of various vasculitides diseases with clinical and pathological features phenotypic features? Or are there dis- have been increasingly discovered. of ANCA-associated disease who were tinctly different diseases? There is a The central role of autoimmunity in determined to be ANCA-negative us- need to better understand and identify ANCA associated vasculitis has been ing conventional clinical assays react- such subgroups of PAN. confirmed by the association with HLA ed with a specific MPO epitope when a Even though PAN is rare, well-de- polymorphisms; interestingly, the three highly sensitive epitope-excision meth- signed multicentre studies might iden- main AAV subtypes are associated with od was used; this epitope was blocked tify the clinical characteristics defining distinct HLA variants, i.e., GPA with from reacting with ANCA IgG in se- possible subphenotypes. As a first step HLA-DP1, microscopic polyangiitis rum because of competitive binding by for this collaboration, we collated de- with HLA-DQ and EGPA with HLA- a fragment of ceruloplasmin, which is a mographic and clinical features of PAN DRB4 (59). A genome wide association natural inhibitor of MPO (49). patients from the UK and Turkey and study of HCV and cryoglobulin-related Although EGPA is characterised by eo- compared these parameters (52). Turk- vasculitis identified associations with sinophilia and tissue eosinophil infiltra- ish PAN patients were younger by 10 cryoglobulin-related vasculitis identi- tion there are overlapping features with years at disease onset and had more fied by SNPs near NOTCH4 and MHC GPA and MPA particularly in the mi- monogenic disease. In the Turkish co- Class II genes (60). In Takayasu’s ar- nority of EGPA patients who are ANCA hort the presence of genetic factors that teritis, genetic susceptibility loci with positive. ANCA-negative EGPA may predispose to inflammation might have a genome-wide level of significance in have features of medium sized artery been effective in the younger onset due IL6 (rs2069837), and an intergenic lo- involvement, indistinguishable from to the relevant genetic load (53). A net- cus on chromosome 21q22 (rs2836878) PAN. In fact several patients have been work for next steps for identification of were identified (61). In genome-wide reported to manifest systemic vascu- subgroups and genetics studies in PAN association studies (GWAS) of Kawa- litis but have no features that put the was established. saki syndrome, novel susceptibility disorder definitively into a single cat- Using newer and different modalities genes associated with coronary artery egory or whose manifestations overlap might highlight the differences/simi- aneurism formation were identified several of the well-defined and dis- larities of subgroups. Histopathological (62). Study of the genetics of PAN is tinct syndromes, e.g. PAN or EGPA or evaluations could be useful not only for limited by its rarity, the small number MPA (50, 51). Although the 1990 ACR differential diagnosis but also therapeu- of familial cases and the complexity Classification Criteria of PAN did not tic approach. Masuda et al. studied 19 of disease phenotypes. A multinational include the ANCA test, or MPA as a di- patients who had undergone autopsy collaborative effort will be required to agnostic category, subsets of PAN were with a diagnosis of cutaneous PAN (54). perform a GWAS study in PAN. noticed (12). A patient group with neu- The cutaneous PAN group showed high ropathy and weight loss >6.5 kg, nega- matrix metalloproteinase-1 and TNF-α Conclusion tive arteriography and artery biopsy is expressions and decreased smoothelin The terminology of peri/polyarteritis one of those groups and could be in expression in the vascular wall. On the nodosa and the corresponding patient

S-140 Clinical and Experimental Rheumatology 2018 Definition of polyarteritis nodosa-subphenotypes / O. Karadag & D. Jayne groups has changed over the last two tis B antigen/antibody immune complexes for familial Mediterranean fever. Nat Genet centuries. However, there is no uniform in the pathogenesis of vascular and hepatic 1997; 17: 25-31. manifestations in polyarteritis nodosa. J Clin 27. AKSU K, KESER G: Coexistence of vascu- definition of PAN associated with a Pathol 1974; 27: 863-8. litides with familial Mediterranean fever. condition exhibiting protean and over- 11. van der WOUDE FJ, RASMUSSEN N, Rheumatol Int 2011; 31: 1263-74. lapping clinical manifestations, and no LOBATTO S et al.: Autoantibodies against 28. ZHOU Q, YANG D, OMBRELLO AK et al.: specific serologic diagnostic tests have neutrophils and monocytes: tool for diagno- Early-onset and vasculopathy associ- sis and marker of disease activity in Wegen- ated with mutations in ADA2. 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